Project Summary: The long-term goal of this research is to engineer new biomaterials formulated from self- assembling peptides or peptidomimetics to produce synthetic extracellular matrices (ECMs) useful for tissue repair or regeneration. Such approaches will enable new therapies for periodontal wound healing, facial soft tissue reconstruction, and other applications in regenerative medicine and tissue engineering. As scaffolds for these therapies, peptide-based biomaterials possess advanced properties such as tunable bioactivity, highly controllable fibrillar architectures, and complex presentation of many different peptides to provide multiple receptor-specific interactions between cells and the material. A critical issue, however, revolves around designing these scaffolds so that they are well-tolerated immuno|ogically, because peptide immunogenicity can be significantly enhanced by multimerization or assembly. To address the dual issues of designing self-assembling peptide biomaterials from native peptides likely to be tolerated while concurrently understanding how peptide designs impact immunoreactivity, the research is subdivided into the following two aims: Aim 1) Design minimally modified fibrin-inspired oligomerization domains by understanding the impact of amino acid tailoring on folding and multimerization; Aim 2) Determine the immunogenic tolerability of peptide tailoring. These aims will be accomplished by a collaborative team of biomedical engineers, structural biologists, and immunologists by designing a novel series of multimerizing peptides inspired by the protein fibrin, analyzing peptide folding/oligomerization behavior with circular dichroism spectroscopy and analytical ultracentrifugation, and investigating the humoral and cellular immunologic response to the designed peptides in mice. The outcomes of this research include the design of minimally-immunogenic peptides that fold into useful oligomerizing structures and an understanding of how peptide design affects immunoreactivity within these self-assembling systems. Thus, this research will enable future studies in which biomaterials produced from these designed peptide building blocks will be investigated as new scaffolds for regenerative medicine. Relevance: This research is relevant to the public health because it provides new materials for reconstructing damaged or diseased soft tissues. Also, the research will broaden the understanding of how this class of materials interacts with the immune system.